Pancreatic Cancer: MMP3 Drives Progression Through Oncogenic Protein Activation

Dr. Derek Radisky PhD Associate Professor and Consultant Mayo Clinic Cancer CenterMedicalResearch.com Interview with
Dr. Derek Radisky PhD
Associate Professor and Consultant
Mayo Clinic Cancer Center

MedicalResearch: What are the main findings of the study? 

Dr. Radisky: The study used human tissue biopsies to find that production of matrix metalloproteinse-3 (MMP3)  in pancreatic cancer biopsies was associated with poorer patient prognosis, and showed through transgenic animal and cell culture experiments that this was due to activation of the oncogenic protein Rac1b.  The study thus identifies an MMP3-Rac1b signaling axis that drives pancreatic cancer progression.

MedicalResearch: Were any of the findings unexpected?

Dr. Radisky: It was previously known that MMP3 was produced by pancreatic cancer cells, but the significance of this finding was unknown.  We now show that increased expression of MMP3 specifically drives an oncogenic pathway in pancreatic cancer.  We further elucidate pathways activated by MMP3/Rac1b in pancreatic cancer, showing that they are associated with disruptions of the tumor microenvironment that facilitate cancer progression.


MedicalResearch: What should clinicians and patients take away from your report?

Dr. Radisky: Current improvements in treatment of all kinds of cancers are coming from development and  use of drugs that target specific cancer-associated pathways-here we identify a previously unknown pathway that presents several new points for targeted therapeutic intervention.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Radisky: The most important next step will be to develop reagents that specifically block the oncogenic functions of MMP3 and Rac1b.  Previous efforts to target MMPs have not been successful, I part because of lack of specificity for a particular MMP, and as a family, MMPs have bot pro- and anti-tumorigenic functions.  Current investigations, however, are leading to development of reagents with much greater specificity.

Additionally, development of reagents that specifically target Rac1b is now a strong priority.

Finally, additional patient-based studies are warranted to determine whether MMP3/Rac1b expression can provide insight into response to existing pancreatic cancer treatments.

Citation:
Tumor Cell-derived MMP-3 Orchestrates Rac1b and Tissue Alterations that Promote Pancreatic Adenocarcinoma

Mol Cancer Res. 2014 May 21. pii: molcanres.0557.2013. [Epub ahead of print]

Mehner C1, Miller E1, Khauv D1, Nassar A2, Oberg AL3, Bamlet WR3, Zhang L4, Waldmann J5, Radisky ES1, Crawford HC1, Radisky DC6.

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